Provigil (modafinil) Counteracts SSRI Side Effects

Action Points

Definitive conclusions cannot be drawn from this preliminary study, which was uncontrolled and examined a very small number of patients.

Further research is needed to determine whether physicians should consider Provigil (modafinil) in patients on an SSRI regimen who report excessive somnolence and fatigue.

Do not prescribe this drug in combination with other medications that are metabolized through the cytochrome P450 and cytochrome CYP2C19 pathways.

The somnolence and fatigue frequently reported by patients taking SSRIs interfere with patient compliance, diminish quality of life, and could possibly lead to relapse.

In order to address this problem, a team of researchers headed by Dr. Thomas L. Schwartz of the SUNY Upstate Medical Center in Syracuse, New York, investigated whether Provigil (modafinil) could counteract these side effects.

Modafanil is a nonamphetamine "wake-promoting agent," and is a popular and well-tolerated treatment for the sleepiness associated with narcolepsy. Its mechanism of action is not well understood, but it may increase dopaminergic signaling or the activity of wake-promoting histamine neurons in the tuberomammillary nucleus.

This small, prospective, open-label, uncontrolled study enrolled twenty patients, sixteen of whom completed the study. All enrollees were receiving ongoing SSRI treatment for major depressive disorder and had experienced sedating side effects as a consequence of ongoing antidepressant therapy. These patients were given Provigil (modafinil) once-daily, and their symptoms were assessed at baseline and then weekly for 3 weeks. Dosage ranged from 50 mg to 400 mg, depending on physician discretion and patient tolerability.

Results are as follows:

Provigil (modafinil) significantly improved overall depressive symptoms, as shown by reductions on the mean Hamilton Rating Scale for Depression scores. At the final visit, 71% of patients had reduced their scores by 50% or more (P = .0001).

The drug also improved subjective estimates of wakefulness on the Epworth Sleepiness Scale. At the final visit, mean scores decreased by about seven points from baseline (P < .001).

At the final visit, patients reported significant increases in overall health status and health-related quality of life. Patients' SF-12 scores decreased from an average score of about 47 at baseline to an average score of about 6 at the final visit (P = .007).

The drug was well-tolerated: there were no serious adverse events and no patients discontinued treatment because of adverse events.

"The fact that adjunctive modafinil not only alleviated SSRI-induced side effects but also improved physical and mental health-related quality of life suggests that its addition to antidepressant therapy may be of benefit in promoting patient adherence by reducing noncompliance due to medication side effects as a potential cause for relapse," the study authors wrote.

The study advises caution when combining Provigil (modafinil) with other drugs. The drug is hepatically metabolized and induces several cytochrome P450 enzymes, thus decreasing the effectiveness of oral contraceptives and perhaps other medications that are metabolized by cytochrome P450 and cytochrome CYP2C19 pathways.

The researchers acknowledge that the study is limited by its small sample size, lack of control group, and open-label methodology, but they say their positive findings warrant further, systematic study.

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine